Search

Purpose: The causal relationship between breast cancer and its estrogen receptor (ER) subtypes and neutropenia and agranulocytosis is unclear., Methods: In two-sample Mendelian randomization (MR), we used inverse variance weighting (IVW), Bayesian weighted MR (BWMR), MR-Egger, weighted median, simple mode, and weighted mode methods to analyze causality for ER-positive breast cancer, ER-negative breast cancer, overall breast cancer, and drug-induced neutropenia and agranulocytosis. To validate the results, we performed the analysis again using GWAS data on neutropenia from different databases. In multivariable MR (MVMR), we assessed the independent effects of ER-positive and ER-negative breast cancer on causality., Results: Two-sample MR analysis showed a causal relationship between ER-positive breast cancer (IVW odds ratio (OR) = 1.319, P = 7.580 × 10 -10 ), ER-negative breast cancer (OR = 1.285, P = 1.263 × 10 -4 ), overall breast cancer (OR = 1.418, P = 2.123 × 10 -13 ), and drug-induced neutropenia and a causal relationship between ER-positive breast cancer (OR = 1.349, P = 1.402 × 10 -7 ), ER-negative breast cancer (OR = 1.235, P = 7.615 × 10 -3 ), overall breast cancer (OR = 1.429, P = 9.111 × 10 -10 ), and neutropenia. Similarly, ER-positive breast cancer (OR = 1.213, P = 5.350 × 10 -8 ), ER-negative breast cancer (OR = 1.179, P = 1.300 × 10 -3 ), and overall breast cancer (OR = 1.275, P = 8.642 × 10 -11 ) also had a causal relationship with agranulocytosis. MVMR analysis showed that ER-positive breast cancer remained causally associated with drug-induced neutropenia (OR = 1.233, P = 4.188 × 10 -4 ), neutropenia (OR = 1.283, P = 6.363 × 10 -4 ), and agranulocytosis (OR = 1.142, P = 4.549 × 10 -3 ). Heterogeneity analysis and pleiotropy test showed that our results were reliable., Conclusion: Our study provides genetic evidence for a causal association between breast cancer and its estrogen receptor subtypes and neutropenia. In clinical practice, in addition to focusing on therapeutic factors, additional attention should be given to breast cancer patients to avoid severe neutropenia., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Antithyroid drug (ATD)-induced agranulocytosis (TIA) is the most serious adverse effect during ATD treatment of Graves' disease (GD). Previously, the MICA gene was reported to be associated with TIA. MICA protein is an important ligand for the NKG2D protein, which is encoded by the KLRK1 gene and KLRC4-KLRK1 read-through transcription. This study further investigated the association between KLRC4-KLRK1 gene polymorphisms and susceptibility to TIA., Methods: Twenty-eight candidate single nucleotide polymorphisms (SNPs) on KLRC4-KLRK1 read-through transcription were evaluated by the iPLEX MassARRAY system in 209 GD control patients and 38 TIA cases., Results: A significant association of rs2734565 polymorphism with TIA was found (p=0.02, OR=1.80, 95% CI=1.09-2.96). The haplotype C-A-A-C-G, including rs2734565-C, was associated with a significantly higher risk of TIA (p=4.79E-09, OR=8.361, 95% CI=3.737-18.707). In addition, the interval time from hyperthyroidism to agranulocytosis onset was shorter in patients carrying the rs2734565-C allele than in non-carrying groups (45.00 (14.00-6570.00) d vs. 1080.00 (30.00-3600.00) d, p= 0.046), and the interval from ATD treatment to agranulocytosis onset was also shorter in patients carrying rs2734565-C allele (29.00 (13.00-75.00) d vs. 57.50 (21.00-240.00) d, p= 0.023)., Conclusions: The findings suggest that the KLRC4-KLRK1 gene polymorphism is associated with susceptibility and progression of ATD-induced agranulocytosis. Patients carrying the rs2734565-C allele had a higher susceptibility and faster onset time of TIA., Competing Interests: The authors declare that they have no competing interests., (Thieme. All rights reserved.)

Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, p corrected  = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation., (© 2022. The Author(s).)

Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is characterized by severe reduction of circulating neutrophils. Immune-mediated responses have been proposed as a possible mechanism for the pathogenesis of ATD-induced agranulocytosis. Although it has been reported that the HLA class II allele (HLA-DRB1*08:03) was associated with ATD-induced agranulocytosis in multiple populations, the entire HLA region have not been explored in Japanese. Therefore, we performed HLA sequencing for 10 class I and 11 class II genes in 87 patients with ATD-induced agranulocytosis and 384 patients with GD who did not show ATD-induced agranulocytosis. By conducting case-control association studies at the HLA allele and haplotype levels, we replicated the association between HLA-DRB1*08:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10 -7 , odds ratio = 2.80), and identified HLA-B*39:01:01 as an independent risk factor (P = 1.4 × 10 -3 , odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B*39:01:01, we reanalyzed allele frequency data for HLA-B*39:01:01 from previous case-control association studies. The association of HLA-B*39:01:01 was significantly replicated in Chinese (P = 9.0 × 10 -3 ), Taiwanese (P = 1.1 × 10 -3 ), and European populations (P = 5.2 × 10 -4 ). A meta-analysis combining results from the previous and current studies reinforced evidence of the association between HLA-B*39:01:01 and ATD-induced agranulocytosis (P meta  = 1.2 × 10 -9 , pooled OR = 3.66, 95% CI; 2.41-5.57). The results of this study will provide a better understanding of the pathogenesis of ATD-induced agranulocytosis in the context of HLA-mediated hypersensitivity reactions.

Background: Thionamide-induced agranulocytosis (TIA), namely antithyroid drug (ATD)-induced agranulocytosis, is one of the most feared adverse effect of ATDs. It is defined as a granulocyte count of less than 0.5 × 10 9 /L after ATD administration. Several studies reported that TIA is associated with human leukocyte antigen (HLA) and nearby genes. Our previous study found that the susceptibility genes of TIA are similar in north China and European populations., Methods: We evaluated the associations of 23 candidate single nucleotide polymorphisms (SNPs) in 37 patients with TIA and 254 patients with Graves' disease (GD) as controls by iPLEX MassARRAY system., Results: Five SNPs in the MHC class I polypeptide-related sequence A(MICA) genes [rs4349859 (p = 1.43E-7); rs145575084 (p = 5.79E-6); rs116135464 (p = 3.70E-5); rs148015908 (p = 3.79E-5) and rs189600525 (p = 2.15E-4)] were found to be significantly associated with TIA after Bonferroni correction. After combining with previous data of rs4349859 and HLA-B*27:05, the haplotype analysis showed that patients carrying P-A-C-A-T-T-A haplotype have a higher risk of TIA (p = 9.76E-7; OR = 14.85, 95% CI 3.63-60.77)., Conclusion: Our findings suggest that five high linked SNPs of MICA gene are significantly associated with susceptibility to TIA.

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations ( p < 1 × 10 -7 ) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41-6.68, p = 1.01 × 10 -7 ) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, p = 5.75 × 10 -7 ), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

Aims: Antithyroid drug (ATD)-induced agranulocytosis is a life-threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in ATD-induced agranulocytosis. To examine the associations between HLA genotypes and ATD-induced agranulocytosis, we conducted a systematic review and meta-analysis of pharmacogenomics studies., Methods: We searched the MEDLINE, Embase and CENTRAL databases on 16 June 2018 for case-control studies on the associations between HLA genotypes with ATD-induced agranulocytosis. The Newcastle-Ottawa scale was used to evaluate the risk of bias of included studies. We conducted random-effects model meta-analysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs) to determine the associations between HLA genotypes and ATD-induced agranulocytosis., Results: We included 5 studies with 142 ATD-induced agranulocytosis cases, 1529 matched ATD-tolerant controls and 5945 healthy controls. The risk of bias of included studies was generally low. ATD-induced agranulocytosis was associated with HLA-B*27:05 (OR 10.97; 95% CI 0.75-159.99), HLA-B*38:02 (OR 19.85; 95% CI 7.94-49.57) and HLA-DRB1*08:03 (OR 5.29; 95% CI 3.44-8.14). After excluding propylthiouracil, the associations of ATD-induced agranulocytosis with HLA-B*27:05 and HLA-B*38:02 were strengthened (OR being 20.61 (95% CI 5.21-81.58) and 40.59 (95% CI 13.24-124.47), respectively). The associations of ATD-induced agranulocytosis with HLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 remained significant when compared to population controls (OR being 7.37 (95% CI 3.86-14.07), 36.43 (95% CI 12.80-103.70) and 5.42 (95% CI 2.36-12.47), respectively). HLA-B*27:05, HLA-B*38:02, and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis., Conclusions: HLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis., (© 2019 The British Pharmacological Society.)

Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

Clozapine is the only effective antipsychotic for treatment-resistant schizophrenia but remains widely under prescribed, at least in part due to its potential to cause agranulocytosis and neutropenia. In this article, we provide an overview of the current understanding of the genetics of clozapine-associated agranulocytosis and neutropenia. We now know that the genetic etiology of clozapine-associated neutropenia is complex and is likely to involve variants from several genes including HLA-DQB1, HLA-B and SLCO1B3/SLCO1B7. We describe recent findings relating to the Duffy-null genotype and its association with benign neutropenia in individuals with African ancestry. Further advances will come from sequencing studies, large, cross-population studies and in understanding the molecular mechanisms underlying these associations.

Some effective antithyroid drugs (ATDs) have been widely used for patients with Graves' disease (GD) but are associated with ATD-induced agranulocytosis. We selected 29 ATD-induced agranulocytosis patients, 44 ATD-induced neutropenia patients, and 140 GD controls among the Chinese Han population who were recruited at the First Affiliated Hospital of Xi'an Jiao Tong University. We assessed their response to ATDs treatment by performing genotyping for a candidate gene association study of samples from patients receiving treatment. Human flavin-containing monooxygenase 3 (FMO3), which is the major hepatic enzyme involved in the production of N-oxide of trimethylamine, catalyzes the oxygenation of a variety of drug compounds. Six single SNP, genotype, haplotype (HAP), and association analyses of the FMO3 gene with ATD-induced agranulocytosis/neutropenia under different models (i.e., additive, dominant, and recessive models) were performed. Rs1736557, which caused an amino acid variation V257M, showed a strong association between ATD-induced agranulocytosis and GD controls after Bonferroni correction (p = 0.011, OR 2.301, 95% CI 1.201-4.409). The presence of HAP 3 (HAP3) in the FMO3 gene HAP was statistically associated with ATD-induced agranulocytosis (p = 0.038, permutation p value). Our findings indicate that genetic variations in the FMO3 gene are associated with the response to ATDs maintenance treatment in ATD-induced agranulocytosis patients of -Chinese Han population., (© 2019 S. Karger AG, Basel.)

Agranulocytosis is a serious, although rare, adverse reaction to sulfasalazine, which is used to treat inflammatory joint and bowel disease. We performed a genome-wide association study comprising 9,380,034 polymorphisms and 180 HLA alleles in 36 cases of sulfasalazine-induced agranulocytosis and 5,170 population controls. Sulfasalazine-induced agranulocytosis was significantly associated with the HLA region on chromosome 6. The top hit (rs9266634) was located close to HLA-B, odds ratio (OR) 5.36 (95% confidence interval (CI) (2.97, 9.69) P = 2.55 × 10 -8 ). We HLA-sequenced a second cohort consisting of 40 cases and 142 treated controls, and confirmed significant associations with HLA-B*08:01, OR = 2.25 (95% CI (1.02, 4.97) P = 0.0439), in particular the HLA-B*08:01 haplotype HLA-DQB1*02:01-DRB1*03:01-B*08:01-C*07:01, OR = 3.79 (95% CI (1.63, 8.80) P = 0.0019), and with HLA-A*31:01, OR = 4.81 (95% CI (1.52, 15.26) P = 0.0077). The number needed to test for HLA-B*08:01 and HLA-A*31:01 to avoid one case was estimated to be 1,500. We suggest that intensified monitoring or alternative treatment should be considered for known carriers of HLA-B*08:01 or HLA-A*31:01., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: We aimed to determine changes in miR-17-92 cluster expression in serum and granulocytes from patients with antithyroid drug (ATD)-induced agranulocytosis., Methods: In this study, real-time polymerase chain reaction (PCR) was used to detect serum miR-17-92 expression levels in 20 ATD-induced agranulocytosis and 16 control patients. Importantly, dynamic changes in neutrophil counts from granulocytopenia to agranulocytosis were observed in 6 of the 20 patients. miR-17-92 expression levels in granulocytes of those six patients under the granulocytopenia condition were measured and compared with corresponding granulocyte samples after recovery. Additionally, the expression levels of these miRNAs in patients with type I or type II bone marrow characteristics were analyzed, and the correlation between miR-17-92 and serum free thyroxine level was analyzed., Results: We found that levels of miR-17-92 expression decreased in both serum and pre-agranulocytosis granulocytes from patients with ATD-induced agranulocytosis compared with those in serum and granulocytes from both recovered patients and control patients. However, no difference among patients with either type of bone marrow characteristics was observed, and no correlation between serum miR-17-92 and free thyroxine levels was found., Conclusion: In ATD-induced agranulocytosis, expression of the miR-17-92 cluster is reduced in both serum and granulocytes, though this alteration does not correlate with bone marrow characteristics or thyroid function.

Prescription of clozapine is complicated by the occurrence of clozapine-induced reduction of neutrophils. The aim of this study was to identify genetic risk factors in a population of 310 Dutch patients treated with clozapine, including 38 patients developing neutropenia and 31 patients developing agranulocytosis. NQO2 1541AA (NRH quinone oxidoreductase 2; protects cells against oxidative metabolites) was present at a higher frequency in agranulocytosis patients compared with control (23% versus 7%, P=0.03), as was ABCB1 (ABC-transporter-B1; drug efflux transporter) 3435TT (32% versus 20%, P=0.05). In patients developing neutropenia, ABCB1 3435TT and homozygosity for GSTT1 null (glutathione-S-transferase; conjugates reactive clozapine metabolites into glutathione) were more frequent compared with control (34% versus 20%, P=0.05 and 31% versus 14%, P=0.03), whereas GSTM1 null was less frequent in these patients (31% versus 52%, P=0.03). To investigate whether combinations of the identified genetic risk factors have a higher predictive value, should be confirmed in a larger case-control study.

Antithyroid drug (ATD)-induced agranulocytosis is associated with human leukocyte antigen (HLA) and nearby genes in Southeast Asian and European populations. The susceptibility of the Han population from northern China to ATD-induced agranulocytosis has not been reported. We evaluated the associations of genetic variants at the HLA-B and HLA-DRB1 loci and 32 candidate single nucleotide polymorphisms (SNPs) with agranulocytosis in 29 patients with ATD-induced agranulocytosis and in 140 patients with Graves' disease (GD) as controls. All subjects were of Han descent from northern China. HLA-B*27:05 (P = 1.10 × 10 -4 ), HLA-B*38:02 (P = 2.41 × 10 -4 ) and HLA-DRB1*08:03 (P = 1.57 × 10 -3 ) were susceptibility HLA variants for ATD-induced agranulocytosis. All subjects carrying the HLA-B*27:05 allele had agranulocytosis. The odds ratios (ORs) comparing allele carriers to non-carriers were 66.24 (95% confidence interval (CI): 3.54-1239.66) for HLA-B*27:05, 7.525 (95% CI: 2.294-24.68) for HLA-B*38:02 and 4.316 (95% CI: 1.56-11.93) for HLA-DRB1*08:03. Two SNPs, rs2596487 (OR = 4.196, 95% CI = 2.086-8.441, P = 2.08 × 10 -5 ) and rs2228391 (OR = 3.621, 95% CI = 1.596-8.217, P = 1.2 × 10 -3 ), were independently associated with ATD-induced agranulocytosis. Subjects carrying the 'A' allele of rs1811197 or HLA-B*38:02 showed lower minimum granulocyte counts than non-carriers (P = 4.74 × 10 -4 and P = 7.39 × 10 -4 , respectively). Our findings support the association between genetic variations of HLA-B and HLA-DRB1 with ATD-induced agranulocytosis in a Han population from northern China.

Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts ( RAGE ) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target., Competing Interests: The authors declare that no competing interests exist.

Background: Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine., Methods: To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects., Results: We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 × 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 × 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 × 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3~15.8) was approximately double that in CIG (OR: 4.4~7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) ~50% of CIG subjects would be non-CIA; and 2) ~60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA., Conclusions: Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event.

Background: Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03. We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population., Methods: We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count ≤0·5 × 10(9)/L [≤500/μL]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p<5 × 10(-8)., Findings: Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3·24 (95% CI 2·31-4·55, p=1·20 × 10(-11)) for HLA-B*27:05 and 3·57 (2·61-4·90, p=2·32 × 10(-15)) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27:05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27:05 was 7·30 (3·81-13·96) when antithyroid drug-induced agranulocytosis was compared with population controls (p=1·91 × 10(-9)) and 16·91 (3·44-83·17) when compared with a small group of hyperthyroid controls (p=5·04 × 10(-4)). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4·73, 95% CI 3·00-7·44, p=1·92 × 10(-11)) and rs199564443 (17·42, 7·38-41·12, p=7·04 × 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5·27, 3·06-9·10, p=2·35 × 10(-9)) which was in moderate linkage disequilibrium with HLA-B*27:05. In heterozygous carriers of all three SNPs, the predicted probability of antithyroid drug-induced agranulocytosis was about 30% (OR 753, 95% CI 105-6812). To avoid one case of agranulocytosis, based on the possible risk reduction if all three SNPs are genotyped and carriers are treated or monitored differently from non-carriers, roughly 238 patients would need to be genotyped., Interpretation: In white European people, antithyroid drug-induced agranulocytosis was associated with HLA-B*27:05 and with other SNPs on chromosome 6. In the future, carriers of these variants could be placed under intensified monitoring or offered alternative treatment for hyperthyroidism., Funding: Swedish Research Council, Swedish Heart and Lung Foundation, Clinical Research Support at Uppsala University, German Federal Institute for Drugs and Medical Devices, Carlos III Spanish Health Institute, European Regional Development Fund, UK National Institute for Health Research, The Selander's Foundation, Thuréus Foundation, European Commission, and Science for Life Laboratory., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high., (© 2015, The American Society for Clinical Pharmacology and Therapeutics.)

Clozapine is the only evidence-based therapy for treatment-resistant schizophrenia, but it induces agranulocytosis, a rare but potentially fatal haematological adverse reaction, in less than 1% of users. To improve safety, the drug is subject to mandatory haematological monitoring throughout the course of treatment, which is burdensome for the patient and one of the main reasons clozapine is underused. Therefore, a pharmacogenetic test is clinically useful if it identifies a group of patients for whom the agranulocytosis risk is low enough to alleviate monitoring requirements. Assuming a genotypic marker stratifies patients into a high-risk and a low-risk group, we explore the relationship between test sensitivity, group size and agranulocytosis risk. High sensitivity minimizes the agranulocytosis risk in the low-risk group and is essential for clinical utility, in particular in combination with a small high-risk group.

Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10(-32)) and HLA-DRB1*08:03 (Pcombined=1.83 × 10(-9)) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10(-21), 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.

Background: Drug-induced agranulocytosis is a recognized adverse drug event associated with serious infectious complications. Levamisole is an antihelminthic and immunomodulator withdrawn from North American markets in 2005 after reports of agranulocytosis. Previous studies of levamisole, suggest that the human leukocyte antigen (HLA)-B27 confers a genetic predisposition to this adverse drug event. Since 2009, emergency room visits due to agranulocytosis in individuals consuming levamisole-adulterated crack-cocaine have increased., Methods: We performed a case-control study using a genotyping assay and novel gene chip to test the association between cocaine-associated agranulocytosis (CAA) and HLA-B27 and to identify pharmacokinetic and pharmacodynamic gene variants associated with the phenotype., Results: Fifty-one CAA cases were identified through a provincial physician reporting system between 2008 and 2011. We examined eight of these cases and 26 matched controls. Genotyping revealed a significant association between HLA-B27 and CAA (odds ratio [OR] 9.2, 95% confidence interval [CI], 1.54-54.6). We also observed a similar association with the HLA-B27 tag single nucleotide polymorphism rs4349859 (OR 9.2, 95% CI 1.5-54.6) and rs13202464 (OR 6.7, 95% CI 1.1-41). Further associations were identified with variants in the ARBCC12 (OR 10.0, 95% CI 2.7-36.8) and CYP11A1 (OR 7.4, 95% CI 2.1-26.6) genes, while a novel protective association was observed with variants in the ARDB1 gene (OR 0.06, 95% CI 0.007-0.46)., Conclusions: We confirmed the association of HLA-B27 with CAA and identified additional susceptibility variants. Health care providers should inform people who are identified as having CAA that it is genetically determined and can recur with continued cocaine use. The severity of infections and subsequent hospitalization, and the risk of recurrence may prompt health-promoting behaviour changes of the affected individuals. These genetic associations warrant the attention of public health and knowledge translation efforts to highlight the implications for susceptibility to this severe adverse drug event.

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

Objective: To study the clinical and laboratory characteristics of cases with warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome., Method: An 11-year-old boy was diagnosed as WHIM syndrome and CXCR4 gene mutation analysis was performed., Result: Since 3 years of age, the patient had recurrent fever and persistent cough. Since 6 years of age, he had warts on his fingers, the warts increased gradually. His complete blood count showed: white blood cell (WBC) 0.65×10(9)/L, neutrophil 0.15×10(9)/L, hemoglobin 116 g/L, platelet 200×10(9)/L, reticulocyte 0.62%. Results of serum biochemical tests: total protein (TP) 72.2 g/L (reference value 60 - 80 g/L), albumin 20.4 g/L (reference value 20 - 35 g/L), gammaglobulin 20.4 g/L (reference value 20 - 35 g/L). IgG 5.56 g/L (reference value 7.51 - 15.6 g/L), IgA 0.48 g/L (reference value 0.82 - 4.53 g/L), IgM 0.29 g/L (reference value 0.46 - 3.04 g/L). Peripheral blood lymphocyte subsets: CD3(+)T lymphocyte 43.6% (reference value 64.01% - 75.95%), CD19(+)B lymphocyte 1.00% (reference value 9.02% - 14.1%). Bone marrow smears showed that many of the neutrophils had a reactive appearance, with cytoplasmic vacuolation. Most neutrophils had hypersegmentation with four or five nuclear lobules. In some cells, the filaments connecting the nuclear lobes were long. CXCR4 mutation was detected., Conclusion: WHIM syndrome is a rare immunodeficiency disorder with an autosomal-dominant pattern of inheritance. The disease is less progressive, and may accompany the patients' whole life.

We report the first published case of agranulocytosis induced by omeprazole and its recurrence with esomeprazole, the S-isomer form of omeprazole. Interestingly, we found an homozygotous mutation of CYP2C19*17, responsible for the metabolism of proton pump inhibitors.

Diamond-Blackfan anemia is a congenital hypoproliferative macrocytic anemia and 5q- syndrome myelodysplastic syndrome is an acquired hypoproliferative macrocytic anemia. Their common erythroid phenotype reflects a shared pathophysiology-haploinsufficiency of one of many ribosomal proteins and somatic deletion of one allele of the ribosomal protein S14 gene, respectively. Although these abnormalities lead to defective ribosome biogenesis, why ribosomal protein hemizygosity results in anemia is not certain. Here, we characterize the hematopoietic phenotype of mice lacking one allele of the ribosomal protein S6 gene. The mice have an erythroid phenotype similar to both Diamond-Blackfan anemia and the 5q- syndrome and lenalidomide therapy improves their anemia., (Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Objective: Clozapine is considered to be the most efficacious drug to treat schizophrenia, although it is underutilized, partially due to a side effect of agranulocytosis. This analysis of 74 candidate genes was designed to identify an association between sequence variants and clozapine-induced agranulocytosis (CIA)., Method: Blood and medical history were collected for 33 CIA cases and 54 clozapine-treated controls enrolled between April 2002 and December 2003. Significant markers from 4 genes were then assessed in an independently collected case-control cohort (49 CIA cases, 78 controls)., Results: Sequence variants in 5 genes were found to be associated with CIA in the first cohort: HLA-DQB1, HLA-C, DRD1, NTSR1, and CSF2RB. Sequence variants in HLA-DQB1 were also found to be associated with CIA in the second cohort. After refinement analyses of sequence variants in HLA-DQB1, a single SNP (single nucleotide polymorphism), 6672G>C, was found to be associated with risk for CIA; the odds of CIA are 16.9 times greater in patients who carry this marker compared to those who do not., Conclusions: A sequence variant (6672G>C) in HLA-DQB1 is associated with increased risk for CIA. This marker identifies a subset of patients with an exceptionally high risk of CIA, 1,175% higher than the overall clozapine-treated population under the current blood-monitoring system. Assessing risk for CIA by testing for this and other genetic variants yet to be determined may be clinically useful when deciding whether to begin or continue treatment with clozapine., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Antipsychotic medication has been enormously helpful in the treatment of psychotic symptoms during the past several decades. Unfortunately, several important side effects that can cause significant morbidity and mortality. The two most common are abnormal involuntary movements (tardive dyskinesia) and weight gain progressing through diabetes to metabolic syndrome. A more rare and life-threatening adverse effect is clozapine-induced agranulocytosis (CIA), which has been linked to clozapine use. Clozapine itself has a unique position among antipsychotic medications, representing the treatment of choice in refractory schizophrenia. Unfortunately, the potential risk of agranulocytosis, albeit small, prevents the widespread use of clozapine. Very few genetic determinants have been clearly associated with CIA due to small sample sizes and lack of replication in subsequent studies. The HLA system has been the main hypothesized region of interest in the study of CIA, and several gene variants in this region have been implicated, particularly variants of the HLA-DQB1 locus. A preliminary genome-wide association study has been conducted on a small sample for CIA, and a signal from the HLA region was noted. However, efforts to identify key gene mechanisms that will be useful in predicting antipsychotic side effects in the clinical setting have not been fully successful, and further studies with larger sample sizes are required.

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis that in many cases is caused by mutations of the ELANE gene, which encodes neutrophil elastase (NE). Recent data suggest a model in which ELANE mutations result in NE protein misfolding, induction of endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and ultimately a block in granulocytic differentiation. To test this model, we generated transgenic mice carrying a targeted mutation of Elane (G193X) reproducing a mutation found in SCN. The G193X Elane allele produces a truncated NE protein that is rapidly degraded. Granulocytic precursors from G193X Elane mice, though without significant basal UPR activation, are sensitive to chemical induction of ER stress. Basal and stress granulopoiesis after myeloablative therapy are normal in these mice. Moreover, inaction of protein kinase RNA-like ER kinase (Perk), one of the major sensors of ER stress, either alone or in combination with G193X Elane, had no effect on basal granulopoiesis. However, inhibition of the ER-associated degradation (ERAD) pathway using a proteosome inhibitor resulted in marked neutropenia in G193X Elane. The selective sensitivity of G913X Elane granulocytic cells to ER stress provides new and strong support for the UPR model of disease patho-genesis in SCN.

Pearson syndrome is a multiorgan mitochondrial cytopathy that results from defective oxidative phosphorylation owing to mitochondrial DNA deletions. Prognosis is severe and death occurs in infancy or early childhood. This article describes 2 cases with a severe neonatal onset of the disease. A review of the literature reveals the atypical presentation of the disease in the neonatal period, which is often overlooked and underdiagnosed.

The incidence of drug-induced neutropenia has not changed in the western hemisphere over the last 30 years. Yet, the drug panorama has changed considerably. This implies that host factors may play an intriguing role for this idiosyncratic reaction. The knowledge as to mechanisms for the reaction has advanced with emerging understanding of neutropoiesis and immune regulation. Nonetheless, it is still remarkably difficult to pinpoint why and how a drug causes this unexpected, severe adverse event in a patient. Patient characteristics, e.g. genetics, appear to be keys for better understanding, predictions and prevention. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.

Clozapine-induced agranulocytosis (CiA) is a potentially life-threatening pharmacological adverse drug reaction, which limits a broader application of this highly effective atypical antipsychotic in schizophrenic patients. Although this adverse reaction has been well known for almost 30 years, only few genetically based determinants can be identified to date. Furthermore, owing to rare occurrence, specific clinical course and complexity of pathomechanisms of antipsychotic-induced agranulocytosis, only a few of the findings met the criteria of replication. The most promising susceptibility genes for CiA include genes involved in the human leukocyte antigen system and in specific metabolizing enzyme systems. However, complex idiosyncratic drug reactions such as CiA are considered to be determined by multiple, possibly interacting genetic variations, rather than by a single causative variant.

Clozapine-induced agranulocytosis (CA) is still among the least understood adverse drug reactions in psychopharmacology. In particular, its genetic background is far from being clarified. Within the framework of a case-control study, we performed human leukocyte antigen (HLA) genotyping and haplotype analyses in 42 non-Jewish Caucasian schizophrenic patients (N=42) suffering from CA and 75 non-Jewish Caucasian schizophrenic patients treated with clozapine without developing CA. While controlling for age (P<0.0001) and sex (P=0.835), testing of the alleles from both HLA-loci resulted in borderline results for Cw2 (P=0.085, odds ratio (OR)=0.36, 95% confidence interval (CI): 0.08-1.23), Cw7 (P=0.058, OR=2.0, 95% CI: 0.87-4.63) and DRB5*0201 (P=0.005, adjusted OR=22.15). For haplotype analysis, we obtained significant association results with CA for the two-locus haplotypes HLA-Cw-B (P=0.022) and HLA-DRB5-DRB4 (P=0.050), and for the three-locus haplotype HLA-Cw-B-DRB5 (P=0.030). The complex nature of CA implies that many genes might play a role, but currently, only HLA associations with CA are identified as clinically relevant.

Unlabelled: Congenital neutropenia in man was first reported 50 years ago by the Swedish paediatrician Rolf Kostmann. He coined the term "infantile genetic agranulocytosis" for this condition, which is now known as Kostmann syndrome. Recent studies have demonstrated a lack of antibacterial peptides and severe periodontitis in these patients despite recombinant growth factor treatment. Moreover, an increased degree of apoptosis of myeloid progenitor cells in the bone marrow has been shown., Conclusion: Future studies should aim to clarify the underlying molecular genetic defect in Kostmann syndrome.

Background: Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes agranulocytosis in 0.8% of patients. The risk factors for clozapine-induced agranulocytosis (CIA) and the underlying mechanisms are unclear., Aim: To ascertain the genetic and immunological risk factors for CIA, and on the basis of these findings to construct an explanatory model for CIA., Method: We reviewed the literature via Medline (from 1966 to May 2004) and EMBASE (from 1980 to May 2004) using the search terms 'clozapine' and 'agranulocytosis'., Results: We found 8 case-control studies that fulfilled our selection criteria. In schizophrenia patients, CIA appeared to be significantly associated with certain haplotypes of HLA (human leukocyte antigens) genes, with the 4b,3d microsatellite alleles of TNF (tumor necrosis factor), with variant genes of HSP 70 (heat-shock protein), and with NQO2 (dihydronicotinamide riboside quinone oxidoreductase) gene polymorphism. Most of these genetic findings are interrelated. Gene abnormalities of this kind probably play an important aetiological role in CIA and may provide a basis for the construction of an immuno-toxic explanatory model for CIA., Conclusion: It seems likely that CIA can be explained on the basis of genetic and immunotoxic factors. The model should help us to understand how agranulocytosis can be caused by various antipsychotics and how it can be treated. However, it is not yet possible to identify patients who are particularly at risk for CIA.

Drug-induced agranulocytosis is a rare but life-threatening side effect which is possibly based on immunogenetic mechanisms. Some studies regarding agranulocytosis induced by the atypical antipsychotic clozapine dealing with HLA subtyping and enzyme polymorphisms have been performed to elucidate its genetic background. To further screen possibly genetically based pathways of developing agranulocytosis, we assessed clinically relevant polymorphisms of immunoglobulin G or Fcgamma receptors in patients with clozapine-induced (n = 48), ticlopidine-induced (n = 11), thyroid inhibitors-induced agranulocytosis (n = 8), and controls (n = 75). We found significant age-related effects in each of the drug-induced agranulocytoses but no further associations that underline an effect of polymorphisms in FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb genes on drug-induced agranulocytosis. Thus, Fcgamma receptors may not serve as a genetic marker to identify patients at risk for this life-threatening side effect.

Background and Objectives: Cyclic neutropenia (CyN) in childhood and severe congenital neutropenia (SCN) are congenital disorders that cause chronic neutropenia. Mutations in the neutrophil elastase gene, ELA2, have been reported in patients with CyN and in those with SCN. We examined granulopoietic defects in CyN patients with those in SCN patients., Design and Methods: Three patients with CyN and four with SCN were enrolled in this study. Bone marrow cells were enriched based on the expression of CD34, Kit, and granulocyte colony-stimulating factor receptor (G-CSFR). The purified cells were assayed for colony formation, proliferation, and mRNA expression of granular enzymes., Results: All patients showed heterozygous mutations of ELA2. Flow cytometric analysis demonstrated no differences in the frequency of CD34, Kit, and G-CSFR expression between CyN patients and normal subjects. Significant differences in granulocyte/macrophage (GM)-colony formation of CD34(+)/Kit(+) cells were observed among CyN patients, SCN patients, and normal subjects in response to hematopoietic factors. Impaired granulopoiesis was found in both CD34(+)/Kit(+)/G-CSFR(+) and CD34(+)/Kit(+)/G-CSFR- cells in patients with CyN, whereas this impairment was observed only in CD34(+)/Kit(+)/G-CSFR(+) cells in SCN patients, as previously reported. The mRNA expression of granular enzymes in myeloid precursors and the transcription levels during myeloid cell differentiation in CyN patients were comparable to those in normal subjects, in contrast to the abnormal transcription of granular enzymes in SCN patients., Interpretation and Conclusions: These results suggest that the underlying granulopoietic abnormalities differ between CyN and SCN, and emphasize the presence of additional genetic pathophysiology specific to each disease.

Therapy of the atypical antipsychotic drug clozapine is limited by a comparatively high incidence of agranulocytosis in 0.8% of patients. This severe side effect is possibly based on the clozapine-mediated stimulation of cytokines and soluble cytokine receptors release, followed by induction of granulocyte proliferation and induction of myeloperoxidase (MPO) and NADPH-oxidase. Because NADPH-oxidase/MPO may oxidize clozapine to highly reactive nitrenium ions, we investigated the role of hereditary polymorphisms in the NADPH oxidase/myeloperoxidase system in agranulocytosis patients who received clozapine (n = 49), ticlopidine (n = 11), and other drugs prior to the event. The low active MPO -436A allelic variant frequency was 22.2% in cases and 19.9% in controls, but AA carriers were overrepresented among cases compared with the sum of AG and GG-carriers (odds ratio 4.16, 95% confidence limits 0.86-20.3, P = 0.056). Particularly in clozapine-induced agranulocytosis, this finding was most pronounced (P = 0.04). In the CYBA gene, encoding the p22phox subunit of the NADPH-oxidase, 2 polymorphisms were investigated. C242T (His72Tyr) had an allele frequency of 31.9% and 32.2% (P = NS) and A640G in the 3'-UTR was less frequent in cases (48.7%) than controls (60.0%), odds ratio 0.63 (0.39-1.02), P = 0.048. CYBA 640GG-carriers were marginally less frequent in cases compared with controls (28.2% vs. 38.7%, P = 0.062). Sequencing the entire coding region of the NADPH subunit CYBB (gpS1phase) disclosed that CYBB is a highly conserved gene, which does not represent a risk factor for clozapine-induced agranulocytosis. The impact of the polymorphic myeloperoxidase, however, needs further verification to predict a patient's risk to develop drug-induced agranulocytosis.

Clozapine is a dibenzodiazepine neuroleptic with atypical pharmacological and clinical profiles. Treatment with this drug may be complicated with agranulocytosis (AGR). It is likely that defective oxidative mechanism may be the cause of AGR. A candidate gene, dihydronicotinamide riboside (NRH) quinone oxidoreductase 2 (NQO2), which is involved in detoxification of drugs, was selected. This gene has been mapped to the short arm of chromosome six. The gene was studied by single-strand conformation polymorphism analysis and direct sequencing in 98 schizophrenic patients that were treated with clozapine. Eighteen of these patients developed AGR. Ten polymorphisms in the coding regions, in intron 1, and in the promoter region were found, two of which were novel. Comparisons of the polymorphisms in the first intron in AGR patients and controls suggested that this site might be connected with AGR. Quantitative reverse transcriptase-polymerase chain reaction analysis showed that the level of NQO2 mRNA is low in AGR patients compared with the control group. Such a reduction in message suggests that the NQO2 gene may be involved in the development of clozapine-induced AGR.

The morphologic characteristics of bone marrow aspirates from patients recovering from acute agranulocytosis may be closely similar to the pattern observed in cases of acute promyelocytic leukemia (APL). The clinical manifestation also can be ambiguous in a substantial number of cases. The immunophenotypic features of bone marrow from 5 patients recovering from acute agranulocytosis, showing an increase in the percentage of promyelocytes (26%-66%), were compared with the immunophenotype of 31 consecutive patients with APL whose diagnosis was confirmed by PML-RAR alpha gene rearrangement. All markers were similarly expressed, except for CD117 and CD11b. CD117 was positive in 24 (77%) of the APL cases and in none of the acute agranulocytosis cases. On the other hand, CD11b was positive in 5 (100%) of the acute agranulocytosis cases and in only 2 (6%) of the APL cases. Thus, the CD117-CD11b+ phenotype was detected in all patients recovering from agranulocytosis and in only 1 (3%) of 31 APL cases. Therefore, we suggest that the combination of both markers is helpful in the differentiation of APL from recovering benign myeloid proliferation.

The field of phagocytic disorders has attained major biologic and clinical significance in the past 40 years. The development of exciting new techniques in molecular biology and the cellular physiology of signal transduction have made it possible to identify the genetic defects involved in many of these disorders. Moreover through immunopharmacologic intervention, bone marrow or peripheral or cord blood stem cell transplantation along with the prospect of gene therapy, we have begun attempts to at least partially correct genetic defects in cell development and activation pathways in the entire spectrum of phagocyte disorders. Carrier detection and prenatal diagnosis employing with chain reaction techniques or direct nucleotide sequencing in fetal blood have made these diseases potentially preventable or treatable in utero or shortly after birth.

Unlabelled: In 1956 Rolf Kostmann reported on six children with severe neutropenia associated with a block in myelopoiesis at the promyelocyte/myelocyte stage and an autosomal recessive inheritance. He named the new syndrome infantile genetic agranulocytosis. Today it is known as Kostmann's syndrome or severe congenital neutropenia. In 1975 an additional 10 cases from northern Sweden were published. This article reports on the only long-term survivor from the 1975 report plus another five patients born after 1975 who belong to the original "Kostmann family". Treatment and survival have changed dramatically since Kostmann's first publication. In the pre-antibiotic era, Kostmann's syndrome was inevitably fatal during the first year of life., Conclusion: Since the introduction of recombinant human granulocyte colony-stimulating factor (G-CSF) about 10 y ago, most patients now enjoy a normal life span and a greatly improved quality of life. Although the threat of death has disappeared, patients still have problems with infections, especially chronic gingivitis and periodontitis. In other groups of severe neutropenia, not related to the original "Kostmann family", an increased incidence of myeloid leukaemia has been observed. However, in this small cohort none of the children on chronic G-CSF therapy have developed malignancies.